The field of the invention is the major histocompatibility complex class II antigens and immune disorders.
Autoimmunity implies that an immune response has been generated against self-antigens (autoantigens). Central to the concept of autoimmunity is the breakdown in the ability of the immune system to differentiate between self- and non-self antigens. An abnormal immune response to self-antigens implies that there is a loss of tolerance.
The major histocompatibility complex (MHC) class II molecules are important for interactions between immune cells, particularly in antigen presentation to T cells. During a normal immune response, MHC molecules present a foreign antigen to a T cell as a non-self antigen. T cells respond by initiating a cascade of immune events that results in the eventual elimination of the foreign molecule. During autoimmune disease, MHC molecules present a self-antigen to the T cells as a non-self antigen, an event that also triggers T cell induced immune activation. However, in this latter case, since the immune response is directed against self-antigens it frequently results in severe damage to tissues and organs.
MHC proteins are highly polymorphic cell surface glycoproteins that bind antigenic peptides and display them at the cell surface (Rothbard and Gefter, 1991, Ann. Rev. Immunol. 9: 527). T lymphocytes initiate immune responses by recognizing a specific peptide bound to an MHC protein. Class I MHC proteins bind to endogenous peptides in the endoplasmic reticulum (Nuchtern et al., 1989, Nature 339: 223; Yewdell and Bennick, 1990, Cell 62: 203), while class II MHC proteins generally bind exogenously derived peptides in a specialized post-Golgi compartment (Guagliardi et al., 1990, Nature 343: 133; Neefjes et al., 1990, Cell 61: 171; Harding et al., 1990, Proc. Natl. Acad. Sci. USA 87: 5553; Davidson et al., 1991, Cell 67: 105; Germain and Hendrix, 1991, Nature 353: 134). Both class I and class II MHC proteins must bind peptides tightly to prevent peptide exchange at the cell surface and inappropriate immune response.
The peptide-binding sites of class I molecules are usually occupied with a mixture of peptides (Bjorkman et al. 1987, Nature 329: 506; Jardetzky et al., 1991, Nature 353: 326; Falk et al., 1991, Nature 351: 290), and class I molecules do not easily exchange or bind peptides in vitro (Chen and Parham, 1989, Nature 337: 743). Studies using mutant cell lines that do not load peptides onto class I molecules have suggested that peptide binding is required for assembly of the class I heterodimer and for stable cell surface expression (Townsend et al., 1989, Nature 340: 443; Townsend et al., 1990, Cell 62: 285; Ljunggren et al., 1990, Nature 346: 476; Ortiz-Navarrete and Hammerling, 1991, Proc. Natl. Acad. Sci. USA 88: 3594).
Class II MHC proteins isolated from lymphoid cells are very stable complexes with antigenic peptides (Buus et al., 1988, Science 242: 1045; Rudensky et al., 1991, Nature 353: 662). Less than 20% of these class II molecules will bind antigenic peptide added in vitro (Watts and McConnell, 1986, Proc. Natl. Acad. Sci. USA 83: 9660; Buus et al., 1987, Immunol. Rev. 98: 115; Jardetzky et al., 1990, Nature 353: 326; O'Sullivan et al., 1990, J. Immunol. 145: 1799; Roche and Cresswell, 1990, Ann. Rev. Immunol. 144: 1849), or in vivo (Ceppellini et al., 1989, Nature 339: 392; Busch and Rotherbard, 1990, J. Immunol. Meth. 134: 1). The peptide-binding sites on the remainder of the proteins are occupied with tightly bound peptides (Tampe and McConnell, 1991, Proc. Natl. Acad. Sci. USA 88: 4661).